Prostacyclin (PGI-2) is a potent inhibitor of platelet aggregation and is a vasodilator. PGI-2 (which is an enol ether) is too short-lived under physiological conditions to be useful as a drug, especially one to be administered orally. PGI is believed to be deactivated by hydrolysis of the enol ether functional group to give 6-keto-PGF-1Alpha, a compound which has been shown to possess little or none of the therapeutic value of PGI-2. Prostacyclin analogues of potential therapeutic value must be prepared, therefore, taking into account reasonable theories of this deactivation pathway. Herein we present new methods for the preparation for screening of prostacyclin analogues from readily available starting materials through routes which are versatile in terms of the number of types of prostacyclin analogue precursors which can be prepared rapidly from common intermediates. In abiological chemical systems, hydrolysis of enol ethers can be slowed remarkably by attachment of electron-withdrawing groups to the double bond. The methods we propose herein enable the preparation of enol ether functionality in prostacyclin analogues by routes compatible with the placement of electron withdrawing groups on the carbons associated with the enol ether double bond of the product. We propose to develop routes for the conversion of readily available prostacyclin precursors to stabilized prostacyclins. These routes are: (1) metal-assisted cyclization of acetylenic alcohols; (2) alkylidene transfer -; (3) carbene complex (or equivalent)- carbonyl coupling; (4) carbene complex (or equivalent)- ylide coupling. We will also continue to study new routes for the synthesis of the prostaglandin precursor for the cyclization route. Prostacyclin analogues, substituted at C-5 with electron-withdrawing groups, will be prepared and tested for stability toward hydrolysis and for beneficial physiological activity.